An Open-Label, Multicenter, Randomized Phase Ib/II Study of Eribulin Mesylate Administered in Combination With Pemetrexed Versus Pemetrexed Alone as Second Line Therapy in Patients With Stage IIIB or IV Nonsquamous Non Small Cell Lung Cancer
Overview
- Phase
- Phase 1
- Intervention
- eribulin mesylate
- Conditions
- Non Small Cell Lung Cancer
- Sponsor
- Eisai Inc.
- Enrollment
- 98
- Primary Endpoint
- Phase 1b: Number of Participants With Dose-Limiting Toxicity (DLTs)
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
The purpose of this study is to determine whether Eribulin Mesylate Administered in Combination with Pemetrexed is safe and tolerable and to gain a preliminary indication of clinical benefit when administered to Patients with Stage IIIB or IV Nonsquamous Non Small Cell Lung Cancer.
Detailed Description
This open-label, multicenter, randomized study will consist of a Phase Ib portion: a safety run-in period with 3 ascending doses of eribulin; and a Phase II portion: a randomized 3-arm design. . Phase Ib-Patients will be recruited into cohorts, into one of two parallel arms evaluating different eribulin dosing schedules (Arm 1: eribulin on Day 1; Arm 2: eribulin on Days 1 and 8), with a minimum of 3 and a maximum of 6 patients per cohort. All patients will receive pemetrexed (500 mg/m2) in combination with eribulin. All patients in a cohort will receive the same dose level of eribulin and there will not be any intra-patient dose escalation. The dose level of eribulin will be escalated for additional cohorts in each of the two arms unless greater than or equal to 2 dose limiting toxicities (DLTs) are reported at the lower dose level(s) prior to enrollment of the next dose level. Phase II- Patients will be randomized in a 1:1:1 ratio to receive either eribulin in combination with pemetrexed, in each of two dosing schedules (Arms 1 and 2), or pemetrexed alone (Arm 3). For both the Phase Ib and II portions, 1 cycle of therapy will last 21 days, with an estimated number of 6 cycles. Radiologic examinations including a computed tomography (CT) scan of the chest, abdomen, and pelvis as appropriate (and CT or magnetic resonance imaging \[MRI\] as appropriate), will be performed during Screening and thereafter every 2 cycles until disease progression.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients may be entered in the study only if they meet all of the following criteria:
- •Male or female patient greater than or equal to 18 years of age;
- •Histologically or cytologically confirmed nonsquamous NSCLC stage IIIB with malignant pleural effusion or stage IV disease not amenable to curative therapy. Patients with history of stage III disease that have relapsed after chemo- and radiotherapy are also eligible;
- •Have at least 1 site of measurable disease by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST) criteria;
- •Have failed 1 prior platinum-doublet containing chemotherapy regimen for stage IIIB with malignant pleural effusion or stage IV nonsquamous NSCLC. One additional cytotoxic regimen is allowed for neoadjuvant, adjuvant, or neoadjuvant plus adjuvant therapy for Phase II patients. For patients enrolled in the Phase Ib portion, a maximum of three total prior regimens is allowed.
- •Definition of a Chemotherapy Regimen: Any platinum-doublet containing chemotherapy, that may also include biological or targeted agents, and/or humanized antibodies, given concomitantly, sequentially, or both, is considered 1 regimen. If, due to toxicity, the dosing of 1 or more of the components must be reduced, or 1 or more of the components of the regimen must be omitted, or 1 of the components must be replaced with another similar drug, the changed version of the original regimen is not considered a new regimen. However, if a new component, dissimilar to any of the original components, is added to the regimen, the new combination is considered a new regimen. If the treatment is interrupted for surgery or radiotherapy, and then continues with an unchanged schedule and components, that treatment is considered as one regimen despite the interruption.
- •Life expectancy of greater than 3 months;
- •Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) less than 1;
- •Patients must have adequate renal function as evidenced by calculated creatinine clearance greater than 45 mL/min per the Cockcroft and Gault formula;
- •Patients receiving daily treatment with non-steroidal anti-inflammatory agents (NSAIDS) are eligible. Patients with creatinine clearance 45-79 ml/min must be able to interrupt NSAIDS 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of pemetrexed;
Exclusion Criteria
- •Patients may be entered in the study only if they meet all of the following criteria:
- •Prior treatment with pemetrexed, epothilone, ixabepilone, patupilone, halichondrin B or halichondrin B-like compounds;
- •Received chemotherapy, targeted therapy, radiotherapy, surgery, or immunotherapy within the 30 days prior to commencing study treatment or have not recovered from all treatment-related toxicities to Grade less than 1, except for alopecia;
- •History of other malignancies except: (1) adequately treated basal or squamous cell carcinoma of the skin; (2) curatively treated, a) in situ carcinoma of the uterine cervix, b) prostate cancer, or c) superficial bladder cancer; or (3) other curatively treated solid tumor with no evidence of disease for greater than 5 years;
- •Presence of brain metastases, unless the patient has received adequate treatment at least 4 weeks prior to randomization, and is stable, asymptomatic, and off steroids for at least 4 weeks prior to randomization;
- •Received treatment in another clinical study within the 30 days prior to commencing study treatment or patients who have not recovered from side effects of an investigational drug to Grade less than 1, except for alopecia;
- •Are currently receiving any other treatment, including palliative radiotherapy for the tumor aside from control of symptoms;
- •Common Toxicity Criteria (CTC) greater than Grade 3 peripheral neuropathy;
- •Require therapeutic doses of vitamin K antagonists;
- •Uncontrolled pleural effusions, ascites, or other third space fluid collections;
Arms & Interventions
Low Dose E7389 in Combination with Pemetrexed
Intervention: eribulin mesylate
Pemetrexed
Intervention: pemetrexed
High Dose E7389 in Cominbation with Pemetrexed
Eribulin mesylate (eribulin; E7389) administered as a 2-5 minute intravenous (IV) bolus in one of two dosing schedules for both the Phase Ib and Phase 2 portions: either Days 1 and 8 of a 21 day cycle in ascending doses of 0.7, 1.1, or 1.4 mg/m2 or on Day 1 of the 21-day cycle at doses at ascending doses of 0.9, 1.4, or 2.0 mg/m2.
Intervention: Eribulin mesylate (eribulin; E7389)
Outcomes
Primary Outcomes
Phase 1b: Number of Participants With Dose-Limiting Toxicity (DLTs)
Time Frame: Cycle 1 (cycle length=21 days)
DLT were defined as clinically significant adverse events (AE) occurring less than or equal to (\<=) 21 days after treatment. Events as: Non-hematological: 1) Grade greater than or equal to (\>=) 3 peripheral neuropathy; 2) Grade \>=3 nausea, vomiting despite optimal antiemetic treatment; 3) Any nonhematologic toxicity of Grade \>=3, with exceptions as alopecia, single laboratory values out of normal range, hypersensitivity reaction. Hematological:1) Grade 4 neutropenia lasting \>7 days; 2) Febrile neutropenia as fever \>=38.5 degree Celsius with absolute neutrophil count less than (\<)1.0\*10\^9 per liter(/L); 3) Grade 3 thrombocytopenia with nontraumatic bleeding requiring platelet transfusion; 4) Grade 4 thrombocytopenia with/without nontraumatic bleeding. Other 1) Study drug related death; 2) Toxicity that dose escalation committee believed to be DLT that was not covered by above DLT criteria.
Phase 1b: Percentage of Participants With Grade 3 or Higher Treatment Emergent Adverse Events (TEAEs)
Time Frame: From date of first dose up to 30 days after the last dose of study drug in Phase 1b, up to approximately 1 year 2 months
Safety assessment included monitoring and recording all AE including all Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 grades (for both increasing and decreasing severity), and serious adverse events (SAE); regular monitoring of hematology, blood chemistry, and urine values; periodic measurement of vital signs and electrocardiograms (ECGs); and performance of physical examinations. A TEAE was defined as an AE that had on onset date, or a worsening in severity from Baseline (pretreatment), on or after the first dose of study drug up to the end of the study. As per CTCAE, Grade 1 scales as Mild; Grade 2 scales as Moderate; Grade 3 scales as severe or medically significant but not immediately life threatening; Grade 4 scales as life-threatening consequences; and Grade 5 scales as death related to AE.
Phase 2: Percentage of Participants Who Experienced TEAEs
Time Frame: From date of first dose up to 30 days after the last dose of study drug in Phase 2, up to approximately 3 years 6 months
Safety assessment included monitoring and recording all AE including all CTCAE version 4.0 grades (for both increasing and decreasing severity), and SAE; regular monitoring of hematology, blood chemistry, and urine values; periodic measurement of vital signs and ECGs; and performance of physical examinations. A TEAE was defined as an AE that had on onset date, or a worsening in severity from Baseline (pretreatment), on or after the first dose of study drug up to the end of the study.
Secondary Outcomes
- Phase 2: Progression-free Survival (PFS)(From the date of randomization until the earlier of the following two events: the date of PD or the date of death (Up to approximately 3 years 5 months))